View source for Alfatradiol (17α-estradiol)

[[File:17alpha-Estradiol.jpg|thumb|
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! Alfatradiol (17α-estradiol)
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| IUPAC_name = (8''R'',9''S'',13''S'',14''S'',17''R'')-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthrene-3,17-diol
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| Trade name:  Avicis, Avixis, Ell-Cranell Alpha, Pantostin
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| CAS number: 57-91-0
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| Molar mass: 272.388 g·mol−1 
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'''Alfatradiol''', also known as '''17α-estradiol (17α-E2)''', is a naturally occurring enantiomer of 17β-estradiol which differs in stereochemistry at the 17th carbon atom. Unlike other exogenous estrogens, alfatradiol is considered a non-feminizing estrogen because it has a significantly reduced binding affinity for the estrogen receptors compared to 17β-estradiol.<ref>Anstead, G. M., Carlson, K. E., & Katzenellenbogen, J. A. (1997). The estradiol pharmacophore: ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site. Steroids, 62(3), 268—303.</ref><ref name="Perez">Yi, K. D., Perez, E., Yang, S., Liu, R., Covey, D. F., & Simpkins, J. W. (2011). The assessment of non-feminizing estrogens for use in neuroprotection. Brain research, 1379, 61-70. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048764 ] </ref> 

17α-E2 is synthesized in the brain and has a higher binding affinity for the its brain receptor ER-X.<ref>Toran-Allerand, C. D., Tinnikov, A. A., Singh, R. J., & Nethrapalli, I. S. (2005). 17α-Estradiol: a brain-active estrogen?. Endocrinology, 146(9), [tel:3843-3850 3843-3850]. </ref> Because 17α-E2 has neuroprotective properties, it is hypothesized that it could be used as a therapeutic agent for HIV-related neurocognitive disorders.<ref>Datta, G., Miller, N. M., Du, W., Geiger, J. D., Chang, S., & Chen, X. (2021). Endolysosome localization of ERα is involved in the protective effect of 17α-estradiol against HIV-1 gp120-induced neuronal injury. Journal of Neuroscience, 41(50), [tel:10365-10381 10365-10381].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672688 </ref>

=== Mechanism of action ===
17α-E2 is thought to increase AMPK and reduce mTORC1 activity specifically in visceral adipose tissue but not in the liver or skeletal muscle, contrary to other interventions that usually have a system effect such as caloric restriction.<ref name="Stout">Stout, M. B., Steyn, F. J., Jurczak, M. J., Camporez, J. P. G., Zhu, Y., Hawse, J. R., … & Kirkland, J. L. (2017). 17α-Estradiol alleviates age-related metabolic and inflammatory dysfunction in male mice without inducing feminization. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 72(1), 3-15.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155656 ] </ref> In addition, 17α-E2 appears to have a highly sex-specific mode of action.<ref name=":0" /><ref name=":1" /><ref name=":2" />

The beneficial effect of 17-α estradiol on male-specific life expectancy is associated with the fact that it suppresses the age-related increase in the activity of MAPK signaling pathways involved in male inflammatory processes.<ref name="Wink">Wink, L., Miller, R. A., & Garcia, G. G. (2022). Rapamycin, Acarbose and 17α-estradiol share common mechanisms regulating the MAPK pathways involved in intracellular signaling and inflammation. Immunity & Ageing, 19(Article number: 8), 1-20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8805398 ] </ref> In addition, 17α-estradiol appears to protect males from age-related neuroinflammation of the hypothalamus, caused by age-related changes in the activity of the sex gonads.<ref>Debarba, L. K., Jayarathne, H. S., Miller, R. A., Garratt, M., & Sadagurski, M. (2022). 17-α-Estradiol Has Sex-Specific Effects on Neuroinflammation That Are Partly Reversed by Gonadectomy. The Journals of Gerontology: Series A, 77(1), 66-74. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751796 </ref> The study of this phenomenon is important for the field of longevity, since the hypothalamic-pituitary-testicular (HPT) axis plays an important role in the mechanisms of exceptional longevity in men.<ref>Aleksic, S., Desai, D., Ye, K., Duran, S., Gao, T., Crandall, J., ... & Milman, S. (2022). Integrity of hypothalamic–pituitary‐testicular axis in exceptional longevity. Aging cell, e13656.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381897  </ref> It should be noted that chronic treatment with standard doses of 17α-E2 does not adversely affect reproductive fitness in male mice.<ref>Isola, J. V., Veiga, G. B., de Brito, C. R., Alvarado-Rincón, J. A., Garcia, D. N., Zanini, B. M., ... & Stout, M. B. (2022). 17α-estradiol does not adversely affect sperm parameters or fertility in male mice: implications for reproduction-longevity trade-offs. GeroScience, 1-12.</ref>

Interestingly, [[rapamycin]], acarbose and 17α-estradiol might share a common mechanism of action by regulating the ERK1/2 signalling pathway and the p38-MAPK pathway in both sexes, despite the lifespan and IGF1-specific effects of 17α-estradiol.<ref>Wink, L., Miller, R.A. & Garcia, G.G. Rapamycin, Acarbose and 17α-estradiol share common mechanisms regulating the MAPK pathways involved in intracellular signaling and inflammation. ''Immun Ageing'' 19, 8 (2022). <nowiki>https://doi.org/10.1186/s12979-022-00264-1</nowiki></ref>

=== Effects on health and lifespan ===
Aging is associated to an increase in visceral adiposity, [[Metabolic flexibility|metabolic disorders]] and chronic inflammation. In this context, alfatradiol might be a useful therapeutic agent. Animal studies have shown that administration of 17α-E2 has anti-inflammatory effects and can reduce body weight,<ref name="Stout" /> leading to a significant improvement in fasting insulin levels, glycated hemoglobin HbA1C and glucose tolerance.<ref name="Mann">Mann, S. N., Hadad, N., Holte, M. N., Rothman, A. R., Sathiaseelan, R., Mondal, S. A., … & Stout, M. B. (2020). Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α. Elife, 9, e59616. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744101</ref>

Other studies have shown that alfatradiol leads to the production of hepatic insulin-like growth factor (IGF1) in male mice only, and can extend male lifespan by an average of 7% and a maximum of 19% when starting therapy from 16 months, but has no effect in the lifespan of females.<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Kumar, N., Fernandez, E., Flurkey, K., … & Miller, R. A. (2021). 17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. Aging cell, 20(5), e13328.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135004 </ref><ref>Strong, R., Miller, R. A., Antebi, A., Astle, C. M., Bogue, M., Denzel, M. S., … & Harrison, D. E. (2016). Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer. Aging cell, 15(5), 872—884. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013015 </ref><ref name=":0">Garratt, M., Lagerborg, K. A., Tsai, Y. M., Galecki, A., Jain, M., & Miller, R. A. (2018). Male lifespan extension with 17‐α estradiol is linked to a sex‐specific metabolomic response modulated by gonadal hormones in mice. Aging Cell, 17(4), e12786. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052402 ] </ref><ref name=":1">Sidhom, S., Schneider, A., Fang, Y., McFadden, S., Darcy, J., Sathiaseelan, R., … & Stout, M. B. (2021). 17α-Estradiol modulates IGF1 and hepatic gene expression in a sex-specific manner. The Journals of Gerontology: Series A, 76(5), 778—785. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087270 </ref> When administered to elderly male mice (but not females or neutered males), it improved physical performance and age-related sarcopenia by increasing muscle mass and improving motor coordination.<ref name=":2">Garratt, M., Leander, D., Pifer, K., Bower, B., Herrera, J. J., Day, S. M., ... & Miller, R. A. (2019). 17‐α estradiol ameliorates age‐associated sarcopenia and improves late‐life physical function in male mice but not in females or castrated males. Aging Cell, 18(2), e12920. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413653</ref>

Topical treatment with 17α-estradiol was also found to reduce androgenic hair loss in women, though it does not seem to be effective for growing new hair and this is currently its only medical use.<ref>Orfanos, C.E., and L. Vogels. “Lokaltherapie Der Alopecia Androgenetica Mit 17α-Östradiol.” ''Dermatology'', vol. 161, no. 2, 1980, pp. 124–132., <nowiki>https://doi.org/10.1159/000250344</nowiki>. </ref>

== References ==
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